Nanoparticle loaded electrospun implants or coatings for drug release

ABSTRACT

Medical devices, such as stents, including a fibrous layer including particles are disclosed. Methods of forming such medical devices using electrospinning are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 12/888,305 which was filed Sep. 22, 2010 which is a divisionalapplication of U.S. patent application Ser. No. 11/940,158 which wasfiled on Nov. 14, 2007, now U.S. Pat. No. 7,824,601, each of which isincorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to implantable medical devices and methods offabricating that that have an electrospun fibrous network loaded withnanoparticles.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, which areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a constraining member such as aretractable sheath or a sock. When the stent is in a desired bodilylocation, the sheath may be withdrawn which allows the stent toself-expand.

The stent must be able to satisfy a number of mechanical requirements.First, the stent must be capable of withstanding the structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, is due to strength and rigidity around acircumferential direction of the stent. Radial strength and rigidity,therefore, may also be described as, hoop or circumferential strengthand rigidity.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. Generally, it is desirable to minimize recoil. Inaddition, the stent must possess sufficient flexibility to allow forcrimping, expansion, and cyclic loading. Longitudinal flexibility isimportant to allow the stent to be maneuvered through a tortuousvascular path and to enable it to conform to a deployment site that maynot be linear or may be subject to flexure. Finally, the stent must bebiocompatible so as not to trigger any adverse vascular responses.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts or bar arms. The scaffolding canbe formed from wires, tubes, or sheets of material rolled into acylindrical shape. The scaffolding is designed so that the stent can beradially compressed (to allow crimping) and radially expanded (to allowdeployment). A conventional stent is allowed to expand and contractthrough movement of individual structural elements of a pattern withrespect to each other.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. Polymericscaffolding may also serve as a carrier of an active agent or drug.

It may be desirable for a stent to be biodegradable or bioerodible. Inmany treatment applications, the presence of a stent in a body may benecessary for a limited period of time until its intended function of,for example, maintaining vascular patency and/or drug delivery isaccomplished. Therefore, stents fabricated from biodegradable polymerscan be configured to completely erode only after the clinical need forthem has ended.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include a stent comprising:a stent scaffolding composed of a plurality of fibrous structuralelements, wherein the fibrous structural elements are composed of anetwork of polymer fibers, wherein the fibrous structural elementsinclude particles that are encapsulated within the fibers, partiallyencapsulated within the fibers, and entrapped between the fibers of thefibrous layer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a view of a stent.

FIG. 2 depicts an axial cross-section of a stent body formed from afibrous material.

FIG. 3 depicts an axial cross-section of a stent with struts composed ofa fibrous layer and a non-fibrous layer.

FIG. 4 depicts a balloon catheter assembly including a balloon having afibrous layer mounted at an end of a catheter.

FIG. 5 depicts a schematic embodiment of a section of fibrous materialthat includes particles entrapped or dispersed within pores or voidsbetween fibers.

FIG. 6A depicts a schematic illustration of a fiber with a particleencapsulated within the fiber.

FIG. 6B depicts a schematic illustration of a particle partiallyencapsulated in a fiber.

FIG. 6C depicts a schematic embodiment of a section of a fibrousmaterial with particles encapsulated in fibers. FIG. 7 depicts aclose-up view of an axial cross-section of a section of a fibrous layer.

FIG. 8 depicts a schematic of an exemplary electrospinning process forfabricating a fibrous mesh with particles.

FIG. 9A depicts an axial cross-section of a fibrous tubular layer formedfrom the electrospinning process illustrated in FIG. 8.

FIG. 9B depicts an axial cross-section of a stent body having ascaffolding composed of fibrous material which is formed by cutting astent pattern into the fibrous tubular layer shown in FIG. 9A.

FIG. 10A depicts an axial cross-section of a layered tube composed of afibrous tubular layer over a tubular construct.

FIG. 10B depicts a stent body having a scaffolding composed of a layerof fibrous material and a tubular layer formed by cutting a stentpattern into the layered tube shown in FIG. 10A.

FIG. 11 depicts a close-up view of the nozzle from FIG. 8 containingparticles dispersed in a polymer fluid.

FIG. 12 depicts a cross-section of a coaxial nozzle for use in theelectrospinning process depicted in FIG. 8.

FIG. 13 depicts a system including a nozzle for forming fibers and anozzle for spraying particles for depositing over a support.

FIG. 14 depicts an image of an electrospun PLLA conduit or tube.

FIG. 15 depicts the surface structure of an electrospun PLLA conduitimage from scanning electron microscopy (SEM).

FIGS. 16A-C depicts fiber morphology of a laser cut implant.

FIG. 17 depicts an SEM image of approximately 200 nm PLGA nanoparticlesloaded with ApoAl mimetic peptide.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention include a tubular medicaldevice including a device body including a layer of fibrous material.The fibrous layer can make up all or a majority of the device body.Alternatively, a device body can include a fibrous layer disposed over anon-fibrous layer. The fibrous material can be a network or polymerfibers which further includes a plurality of particles. In certainembodiments, the fibers, the particles, or both can include an activeagent or drug for delivery to a vascular lumen upon implantation of thedevice.

As used herein, a “medical device” includes, but is not limited to,self-expandable stents, balloon-expandable stents, stent-grafts,catheter balloons, drug-delivery balloons, and generally tubular medicaldevices. FIG. 1 depicts a view of a stent 100. In some embodiments, astent may include a pattern or network of interconnecting structuralelements 110. Stent 100 may be formed from a tube (not shown). Stent 100includes a pattern of structural elements 110, which can take on avariety of patterns. The structural pattern of the device can be ofvirtually any design. The embodiments disclosed herein are not limitedto stents or to the stent pattern illustrated in FIG. 1. The embodimentsare easily applicable to other patterns and other devices. Thevariations in the structure of patterns are virtually unlimited. A stentsuch as stent 100 may be fabricated from a tube by forming a pattern inthe tube with a technique such as laser cutting or chemical etching.

In some embodiments, a tubular device body, such as a stent body orscaffolding, can be formed substantially or completely of a fibrousnetwork or material that includes particles. In such embodiments, thebody, scaffolding, or substrate of a stent body can be made from afibrous network including particles. In this embodiment, a stent body,scaffolding, or substrate can refer to a stent structure with an outersurface to which no coating or layer of materials different from that ofwhich the structure is manufactured. FIG. 2 depicts an axialcross-section of a stent 150 showing struts 152. Strut 152 is formedfrom a fibrous network or material 154 with particles (not shown).

In additional embodiments, a portion of the medical device can be madeof the fibrous network with particles. In such embodiments, a tubulardevice body can be formed from at least one radial layer of the fibrousnetwork with particles. These embodiments can include a layer of thefibrous network over a non-fibrous layer formed from a polymer or metal.The fibrous layer may be, for example, a luminal layer or abluminallayer of the device. In other embodiments, the fibrous layer may be amiddle layer between non-fibrous luminal and abluminal layers.

FIG. 3 depicts an axial cross-section of a stent 160 with struts 162.Struts 162 include an abluminal fibrous layer 164 and a luminalnonfibrous layer 166. Layer 166 can be a polymer or metal material. FIG.4 depicts a balloon catheter assembly 170 including a balloon 176mounted at an end of a catheter 178. Balloon 176 is composed of aballoon base layer 174 and a fibrous layer 172 disposed over the baselayer. Base layer 174 may be composed of a polymer material typicallyused for fabricating balloons for use in vascular lumens, for example,Pebax from Arkema in Philadelphia, PA. Balloon 176 is depicted in anexpanded configuration to illustrate the layers.

In certain embodiments, the fibrous material is composed of a network ofpolymer fibers with particles included within the network. In someembodiments, a majority of the fibrous network may have fibers in anirregular or random arrangement. In one embodiment, the fibers can bearranged so that the axis of the fibers of the network generally followor are generally parallel to the circumference of the tubular medicaldevice. As is described in more detail below, the fibrous layer isformed by depositing electrospun fibers to form a tubular layer. Thefibrous network is porous with regular irregular voids, spaces, or poresexisting between the fibers of the network. The morphology orarrangement of the fiber axes can be random or partially ordered to formpatterns.

In some embodiments, the particles can be entrapped within the pores orvoids between the fibers of the fibrous network. As used herein,“entrapped” refers to particles positioned and held within voidsexisting between fiber strands and not within fiber strand material.FIG. 5 depicts a schematic embodiment of a section 200 of the fibrousmaterial of fibers 202. Section 200 includes particles 204 entrappedwithin pores or voids 206 between fibers 202. In exemplary embodiments,the void fraction of the fibrous network is less than 20%, 20-50%,50-85%, or greater than 85%.

In other embodiments, the particles can be encapsulated or partiallyencapsulated within the polymer fibers. “Encapsulated” refers to aparticle being completely enclosed within the material or volume of afiber strand. “Partially encapsulated” refers to a particle in whichpart of the volume of the particle is enclosed within the fiber materialor volume of a fiber strand and a part of the particles volume isoutside and not enclosed within the fiber material or volume of thefiber strand. FIG. 6A depicts a schematic illustration of a fiber 210with a particle 212 encapsulated within fiber 210. FIG. 6B depicts aparticle 216 partially encapsulated in a fiber 214. FIG. 6C depicts aschematic embodiment of a section 220 of a fibrous material withparticles 224 encapsulated in fibers 222. In some embodiments, a fibrousnetwork can have particles both entrapped within the network andencapsulated within the fibers of a network.

In exemplary embodiments, the fibers can have a thickness, Tf, as shownin FIG. 6A, of less than 200 nm, 200-500 nm, 500-1000 nm, 1000-5000 nm,5000-10000 nm, 10000-15000 nm, or greater than 15000 nm. Additionally,in exemplary embodiments, the average pore size of the fibrous materialcan be less than 500 nm, 500-1000 nm, 1000-10000 nm, 10-30 μm, 30-70 μm,70-100 μm, or greater than 100 μm.

The size of the particles can be selected to allow encapsulation orentrapment. In particular, the sizes can be selected to be small enoughto allow encapsulation in fibers of the fibrous network, as disclosedabove, or small enough to fit within the pores of the fibrous network,as disclosed above. In exemplary embodiments, the particles can havecharacteristic size, such as a diameter Dp, as shown in FIG. 6A. In someembodiments, the particles can be nanoparticles. A nanoparticle refersto a particle with at least one dimension less than 100 nm. In exemplaryembodiments, the average particles size can be less than 100 nm,100-1000 nm, 1000-5000 nm, 5000-10000 nm, 10000-15000 nm, or greaterthan 15000 nm. Furthermore, the ratio of average void size to averageparticle size can be less than 2, 2-5, or greater than 5. The ratio offiber thickness to average particle size can be less than 0.5, 0.5-1,1-3, 3-5, or greater than 5.

In further embodiments, the particles can be dispersed uniformly ornearly uniformly through a width of a layer of material or dispersedpreferentially near a surface of the layer. FIG. 7 depicts a close-upview of an axial cross-section of a section 230 of a fibrous layer, forexample from FIG. 2 or 3. Particles (not shown) can be distributeduniformly or nearly uniformly through thickness, T_(L), of section 230.Alternatively, particles can be dispersed preferentially or exclusivelyat or near abluminal surface 232. Particles can also be dispersedpreferentially or exclusively at or near luminal surface 234.

In some embodiments, the fibers of the fibrous network can be madepartially or completely from a biodegradable, bioabsorbable, orbiostable polymer. Biostable refers to polymers that are notbiodegradable. The terms biodegradable, bioabsorbable, and bioerodableare used interchangeably and refer to polymers that are capable of beingcompletely degraded and/or eroded when exposed to bodily fluids such asblood and can be gradually resorbed, absorbed, and/or eliminated by thebody. The processes of breaking down and absorption of the polymer canbe caused by, for example, hydrolysis and metabolic processes.

In general, functions performed by a stent, such as drug delivery andproviding patency, are required only for a limited period of time. Forexample, a preferred or required treatment time by a stent may be lessthan 18 months, less than a year, between three and 12 months, or morenarrowly, between four and eight months.

Exemplary polymers for use as fiber material include poly(L-lactide),poly(D,L-lactide), polyglycolide, polycaprolactone, polydioxanone,poly(trimethylene carbonate), poly(4-hydroxybutyrate), poly(esteramides) (PEA), polyurethanes, and copolymers thereof. In particular,poly(L-lactide-co-glycolide) can be used as a fiber material.

In some embodiments, the fibers and particles of the fibrous layer canhave a coating with a synthetic or natural hydrogel. A hydrogel caninclude, but is not limited to, poly(ethylene glycol), poly(vinylalcohol), polyvinylpyrrolidone, hyaluronan, collagen, gelatin, chitosan,alginate, aloe/pectin, cellulose, or polyNIPAAM. In further embodiments,the polymer fibers can be formed from such hydrogels. In additionalembodiments, the hydrogel fibers can be crosslinked.

Additionally, the fibers can be formed from shape memory polymers sothat the fibrous stent body exhibits shape memory effects. Exemplaryshape memory polymers include block copolymers of poly(L-lactide) andpolycaprolactone and polyurethanes, other biostable polyurethanecopolymers, and polyurethane ureas. Shape memory polymers may alsoinclude polymers that possess appropriate thermal transition propertiessuch as glass transition or soft segment melt temperatures that occurnear or slightly (5-20° C.) above physiological temperature (37° C.).

In certain embodiments, the medical device can be designed for thelocalized delivery of a therapeutic agent. In some embodiments, themedical device can have a coating over a portion of the device thatcontains a therapeutic agent. In particular, the coating can be disposedover the fibrous layer. The coating can include a polymer carrier with adrug dispersed within carrier.

As discussed above, in further embodiments, the fibers, particles, orboth can include an active agent or drug that can be released uponimplantation of the medical device. In such embodiments, the activeagent can be mixed or dispersed within the fiber material. The drug canbe delivered through diffusion from fiber material into the patient.Alternatively, the drug may be delivered through degradation of thefiber material.

Additionally, as discussed above, the particles can include an activeagent for delivery into the body of a patient. A drug can beencapsulated or dispersed within, adsorbed to the surface of or absorbedwithin the outside surface of the delivery particle. Alternatively, thedelivery particle may be formed from a precipitate of a bioactive agent,e.g., by a neat bioactive agent or a salt of the bioactive agent withlow solubility.

In some embodiments, the particles can provide for controlled release,sustained release, or both of active agent. Controlled release refers todelivery of an agent at a controlled rate for an extended time.Controlled release of a drug provides a well-characterized andreproducible dosage form. Sustained release refers to release of drugover an extended period of time. In sustained release, the rate andduration of drug are not necessarily designed to achieve a particularprofile. A sustained release profile of an agent or drug can includezero-order release, exponential decay, step-function release, or otherrelease profiles that carry over a period of time, for example, rangingfrom several hours to several years, from several days to severalmonths, and from several days to several weeks. The terms “zero-orderrelease”, “exponential decay” and “step-function release” as well asother sustained release profiles are well known in the art (see, forexample, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz,Ed., Culinary and Hospitality Industry Publications Services).

In some embodiments, the particles may be primarily or completelycomposed of a matrix material with active agents mixed, dispersed, ordissolved in the matrix material. The particle material can be abiostable or biodegradable polymer, metallic, or ceramic. Such particlesmay also be coated with an active agent. The drug in the matrix materialmay be delivered through diffusion through the matrix or degradation ofthe matrix material.

In other embodiments, the particles may encapsulate an active agent.Such particles can have an outer shell of polymer, metal, or ceramicwith an inner compartment containing active agents. The shell can act asa release rate controlling layer. The core of the particles can be areservoir of active agent or a drug-impregnated core of material.

Particles may also include polymerosomes, micelles, vesicles, liposomes,glass (biodegradable and biostable), and micronized or nanoparticulatedrug.

Representative classes of materials that may be used for particlesinclude, but are not limited to, a biostable polymer; a bioabsorbablepolymer; a biosoluble material; a biopolymer; a biostable metal; abioerodible metal; a block copolymer of a bioabsorbable polymer or abiopolymer; a ceramic material such as a bioabsorbable glass; salts;fullerenes; lipids; carbon nanotubes; or a combination thereof.

Further embodiments of the present invention include fabricating amedical device having a fibrous polymeric layer with particles. Incertain embodiments, a method of fabricating can include electrospinningpolymer fibers to form a tubular layer that includes a fibrous networkof the electrospun polymer fibers. The method further includesincorporating a plurality of polymer particles in the fibrous network ofthe electrospun polymer fibers.

Electrospinning refers to a process in which a high voltage is used tocreate an electrically charged jet of polymer fluid, such as a polymersolution or melt, which dries or solidifies to leave a polymer fiber. Asystem for electrospinning can include a syringe, a nozzle, a pump, ahigh-voltage power supply, and a grounded collector. An electrode isplaced into the polymer fluid and the other can be attached to agrounded collector.

The polymer fluid is loaded into the syringe and the liquid is driven tothe catheter tube tip by the syringe pump, forming a droplet at the tip.An electric field is subjected to the end of the catheter tube thatcontains the polymer fluid, which is held by its surface tension. Thefield induces a charge on the surface of the liquid. Mutual chargerepulsion causes a force directly opposite to the surface tension.

As the intensity of the electric field is increased, a hemisphericalsurface of the fluid at the tip of the catheter tube elongates to form aconical shape known as the Taylor cone. With increasing field, acritical value is attained when the repulsive electrostatic forceovercomes the surface tension and a charged jet of fluid is ejected fromthe tip of the Taylor cone. The jet is then elongated and whippedcontinuously by electrostatic repulsion until it is deposited on thegrounded collector. Whipping due to a bending instability in theelectrified jet and concomitant evaporation of solvent or solidificationof melt (and, in some cases reaction of the materials in the jet withthe environment) allow this jet to be stretched to diameters as small asnanometer-scale. The fiber tends to lay itself in an irregular or randomfashion on the grounded collector.

The polymer solution or melt is contained in a glass tube, usually apipette that is connected to a syringe like apparatus. A metering pumpattached to the plunger of the syringe generates a constant pressure andflow of the fluid through the pipette. The driving force is provided bya high voltage source that can generate up to 30 kV, and the setup canbe run on either positive or negative polarity. Adjusting the flow ofthe fluid and the magnitude of the electric field controls the fiberspinning rate.

FIG. 8 depicts a schematic of an exemplary system 250 for fabricating afibrous layer with particles. FIG. 8 shows a syringe 252 that contains apolymer fluid such as a melt or solution 254. A nozzle 256 which can bea needle, catheter tube, or pipette is in fluid communication withpolymer fluid 254 in syringe 252. A high voltage power supply 258 is inelectrical communication with polymer fluid 254 in nozzle 256, as shownby line 260. High voltage source 258 can be in electrical communicationwith polymer fluid 254 through a wire immersed in the fluid. A meteringpump (not shown) attached to a plunger (not shown) of syringe 252generates a constant pressure and flow of the fluid through nozzle 256.

A charged jet of fluid 262 is ejected from nozzle 256, as shown by anarrow 263, due to the pressure from the plunger. A spun fiber 264 isformed from the jet of fluid 262 as solvent in the jet evaporates or thepolymer melt solidifies. Spun fiber 264 is deposited on a cylindricalsupport 266 to form a fibrous material 268. Support 266 is grounded asshown by grounding connection 270. Support 266 rotates, as shown by anarrow 274, and translates, as shown by arrow 276, to allow formation ofa tubular fibrous layer 278. Support 266 can be a rotatable mandrel madefrom material, such as metal or Teflon® for a metal (e.g., stainlesssteel).

Alternatively, support member 266 can be a tubular polymeric or metallicconstruct on which the fibrous material adheres, thereby forming afibrous layer or coating over the polymeric or metallic construct. Thepolymeric or metallic construct can be supported by rotatable mandrel torotate support 266 during formation of tubular fibrous layer 278.

As described in more detail below, the particles can be incorporatedinto fibrous layer 268 is a several ways. In some embodiments, theparticles can be sprayed from the same nozzle 256 as the polymer fluidand deposited on support 266. In other embodiments, the particles can besprayed from a source separate from nozzle 256, for example, anothernozzle. In additional embodiments, the particles can be positioned onthe support prior to forming the fiber mesh. In further embodiments, theparticles can be deposited on the fibrous mesh after its formation.

In the case of a polymer solution as the polymer fluid, exemplarysolvents for use in the polymer solution include acetone, ethanol,ethanol/water mixtures, cyclohexanone, chloroform,hexafluoroisopropanol, 1,4-dioxane, tetrahydrofuran (THF),dichloromethane, acetonitrile, dimethyl sulfoxide (DMSO),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), cyclohexane,toluene, methyl ethyl ketone (MEK), xylene, ethyl acetate, and butylacetate.

An electrospinning process has several process parameters that influencethe properties of the formed fibrous material. Process parameters caninclude electrical potential, flow rate of polymer fluid from thenozzle, concentration of polymer in the fluid, distance between nozzleand the support member or collector, properties of the polymer fluid(e.g., viscosity, conductivity, surface tension), type of polymer,molecular weight of polymer, ambient conditions of process (temperature,humidity, and air velocity in the electrospinning chamber), and motionof the support member or collector.

The electrical potential can be a positive or negative polarity at thenozzle and the opposite polarity at the support or collector. In someembodiments, the support is not charged. The total electrical potentialdifference can be less than 20 V, 10-20 V, or greater than 20 V. Forexample, the nozzle can be +10 V and the support can be (−10) V. For apolymer fluid that is a polymer solution, the concentration of polymerin a solvent of the polymer fluid can be less than 0.5 wt %, 0.5-1 wt %,1-2 wt %, 2-4 wt %, 4-10 wt %, 10-15 wt %, 15-20 wt %, or greater than20 wt %. In exemplary embodiments, the flow rate of fluid from thenozzle can be 0.1-0.5 ml/hr, 0.5-1 ml/hr, 1-2 ml/hr, 2-5 ml/hr, orgreater than 5 ml/hr. The flow rate and concentration can be adjusted toobtain fibers of a desired thickness.

The distance between the nozzle and support (e.g., Lns in FIG. 8) caninfluence the solvent content or degree of solidification of fibersdeposited on the support, which can affect the adhesion of depositedfibers to one another. As the formed fibers fall from the nozzle to thesupport, there is solidification or solvent evaporation from the formedfibers. Thus, the shorter the distance from the nozzle to the support,the lower is the degree of solidification or evaporation of solventwhich can result in greater adhesion of fiber in a formed fibrous layer.The degree of solidification or evaporation also depends on theconcentration of polymer in the polymer solution and the flow rate. Theconcentration, flow rate, and distance between the nozzle and supportcan be adjusted to obtain a desired degree of adhesion. For example, thedistance may be adjusted so that deposited fibers have greater than lessthan 5 wt %, 5-10 wt %, 10-20 wt %, or greater than 20 wt % of solvent.The distance between the nozzle and the support member can be less than6 cm, 6-10 cm, 10-15 cm, 15-20 cm, 20-30 cm, or greater than 30 cm.

In some embodiments, the electrospinning system can be enclosed in achamber and conditions within the chamber can be controlled. Thetemperature in the chamber can be room temperature (20-30° C.) orgreater than room temperature (20-30° C., 30-40° C., or greater than 40°C.). A higher temperature tends to increase the evaporation rate of asolvent in a polymer fluid and decrease the degree the solidification ofa polymer melt.

The rotation rate of the support member can be less than 500 rpm,500-2000 rpm, 2000-5000 rpm, 5000-15000 rpm, or greater than 15000 rpm.

In some embodiments, a tubular body of a device can be formed from thetubular layer made from the electrospinning process. FIG. 9A depicts anaxial cross-section of fibrous tubular layer 278 formed from theelectrospinning process illustrated in FIG. 8. FIG. 9B depicts a stentbody 280 having a scaffolding or struts 282 composed of fibrous material268, formed by cutting a stent pattern into fibrous tubular layer 278shown in FIG. 9A.

In other embodiments, a tubular device, such as stent 160 in FIG. 3 orballoon 170 in FIG. 3, can be formed with at least one fibrous layerformed from the electrospinning process. Balloon 170 can be formed bydepositing electrospun fiber over a balloon, as shown in FIG. 8, with aballoon as the support member. FIG. 10A depicts an axial cross-sectionof a layered tube 285 that includes fibrous layer 278 formed oversupport 266, which corresponds to a tubular construct made from anon-fibrous construct material 267.

FIG. 10B depicts a stent body 290 having a scaffolding or struts 292composed of a layer of fibrous material 268 and a layer of constructmaterial 267 formed by cutting a stent pattern into layered tube 285shown in FIG. 10A.

As indicated above, particles can be incorporated in the fibrous layerin several ways. Additionally, particles can be incorporated into thefibrous layer during its formation or after its formation.

In some embodiments, the particles can be sprayed through the samenozzle as the polymer fluid. In other embodiments, the particles can besprayed from a source separate from nozzle 256, for example, anothernozzle. In additional embodiments, the particles can be positioned onthe support prior to forming the fiber mesh. In further embodiments, theparticles can be deposited on the fibrous mesh after its formation.

In certain embodiments, the particles can be dispersed or suspendedwithin the polymer fluid (e.g., polymer fluid 254 in FIG. 8) in thesyringe and nozzle or the nozzle.

In some embodiments, the suspension of polymer fluid and particles issprayed from the nozzle. The particles may be encapsulated or partiallyencapsulated by fibers formed after exiting the nozzle. Alternatively,particles may be deposited without being encapsulated or partiallyencapsulated. Such particles may be entrapped within voids or poresbetween deposited fibers. FIG. 11 depicts a close-up view of nozzle 256from FIG. 8 showing particles 300 dispersed in polymer fluid 254. A jetis ejected, as shown by an arrow 305, from nozzle 256, and forms fiber264. Particles 304 can be encapsulated within the formed fiber 264.Particles 302 are not encapsulated or partially encapsulated in fiber264.

For embodiments in which the polymer fluid is polymer solution, thesolvent of the polymer solution can be selected to be a nonsolvent forparticles. For example, PEA can be dissolved in ethanol together with asuspension of PLGA nanoparticles and electrospun. Alternatively, thesolvent may be capable of swelling the particle material.

For embodiments in which the polymer fluid is a polymer melt, thetemperature of the polymer melt can be less than the melting temperature(T_(m)) of the particle material to avoid melting of the particle. Forexample, polyglycolide particles (T_(m)=225-230° C., Medical Plasticsand Biomaterials Magazine, March 1998), PLLA particles (T_(m)=173-178°C., Medical Plastics and Biomaterials Magazine, March 1998), orpoly(4-hydroxybutyrate) particles (T_(m)=177° C., Science, Vol. 297 p.803 (2002)) can be loaded within a polycaprolactone melt (T_(m)=58-63°C., Medical Plastics and Biomaterials Magazine, March 1998) to processparticles within polycaprolactone fibers Alternatively, the temperatureof the polymer melt may be above the melting temperature of the particlematerial, but the processing time and conditions allow deposition of theparticle of a desired size.

In further embodiments, the polymer fluid and particles may be sprayedthrough a coaxial nozzle to facilitate encapsulation of the particles inthe fiber. In such embodiments, a polymer fluid is ejected from a nozzleas a shell surrounding a core of particles. FIG. 12 depicts across-section of a coaxial nozzle 310 that has an outer passagewaycontaining polymer fluid 312 and a wall 313 separating the outerpassageway from an inner passageway containing a particle medium 314including particles 315. The particles can be suspended free of anyfluid or be suspended in a fluid. For example, the particles can besuspended in the same solvent as the polymer solution which is free ofpolymer. The particle medium can also be particles suspended in apolymer solution with the same polymer and solvent as in the outerpassageway. The concentration of the polymer in the inner passagewaypolymer solution can be less, the same, or greater than the polymersolution in the outer passageway. As shown in FIG. 12, a jet 318containing polymer fluid and particle medium is ejected from nozzle 310,as shown by an arrow 316, and forms a fiber that includes encapsulatedparticles.

In the embodiments of spraying particles and polymer fluid from the samenozzle, the concentration of polymer in the polymer solution can beadjusted to facilitate encapsulation. It is expected that increasing theconcentration of polymer in the solution increases the degree andlikelihood of encapsulation of particles in the fiber given an increasein fiber diameter.

In further embodiments, particles can be incorporated in the fibrouslayer by spraying the particles from a nozzle separate from polymerfluid nozzle. FIG. 13 depicts a system including nozzle 256 for formingfibers and a nozzle 330 for spraying particles for depositing oversupport 266. Nozzle 330 includes a particle medium 332 that it sprays,as shown by an arrow 334, on fiber layer 278 that is formed on supportmember 266. Particle medium 332 can be particles free of fluid.Alternatively, particle medium 332 can be suspended in a fluid, such asthe same solvent as the polymer solution.

In some embodiments, particle medium 330 can be connected to a highvoltage source of the same polarity as polymer fluid 254 to facilitatedeposition of the particles on support 266. In this case, the jet ofpolymer fluid and particles exiting the respective nozzles have the samecharge. Thus, the particle stream and jet or fiber can repel oneanother, resulting in diversion of particles and fiber away from support266. Thus, an axial distance Dn between the nozzles should be largeenough to reduce or minimize the effect of the repulsion of theparticles stream and jet. Alternatively, the particle stream and jet orfiber can be directed orthogonally. In a further variation, the nozzlescan be positioned on opposite sizes of support member 266 so that thenozzles direct the particle stream and jet toward one another and ontosupport 266.

In additional embodiments of incorporating particles in a fibrous layer,the particles can be deposited on the support member prior to depositingthe fibrous layer. Particles can be applied in a manner that they adhereto the support member. For example, the particles free of a fluid can besprayed onto the support that has been wetted with a fluid, such as asolvent for the particle material. Alternatively, a fluid suspension ofthe particles can be sprayed on the support. For example, acetoneswells, but does not dissolve PLLA. Solvents that swell and dissolvePLLA include chloroform, dichloromethane and hexafluoroisopropanol.

In further embodiments of incorporating particles in a fibrous layer,the particles can be deposited on the fibrous layer after its formation.Particles can be applied in a manner that they adhere to the fibrouslayer. In some embodiments, the particles can be sprayed onto thesupport that has been wetted with a fluid. In one such embodiment, thefluid can be a nonsolvent for the fiber material that swells the fibers.The swelled fibers facilitate the adhesion of the particles to thefiber.

In another such embodiment, the fluid can be a solvent for the fibermaterial that partially dissolves the fiber material. In this case, thepartially dissolved fiber may facilitate at least partial encapsulationof the particles in the partially dissolved fibers. Alternatively, afluid suspension of the particles can be sprayed on the support thatincludes either a nonsolvent that swells the fibers or a solvent thatcan dissolve the fibers.

In other embodiments, the particles can be incorporated afterfabricating a device body from the fibrous layer. In particular, a stentbody can be formed as shown in FIGS. 9A-B and 10A-B, followed byapplication of particles, as described above.

In further embodiments, the polymer fibers can be electrospun from asuspension of particles of an aqueous solution of hydrogel. In suchembodiments, the hydrogel fibers can be crosslinked. The crosslinkedhyrogel fibers may then be swelled to encapsulate or increase the degreeof encapsulation, or completely encapsulate the particles.

“Solvent” is defined as a substance capable of dissolving or dispersingone or more other substances or capable of at least partially dissolvingor dispersing the substance(s) to form a uniformly dispersed solution atthe molecular- or ionic-size level at a selected temperature andpressure. The solvent should be capable of dissolving at least 0.1 mg ofthe polymer in 1 ml of the solvent, and more narrowly 0.5 mg in 1 ml atthe selected temperature and pressure, for example, ambient temperatureand ambient pressure.

Representative examples of polymers that may be used to as a fibermaterial, particle material, or for a non-fibrous layer of a medicaldevice include, but are not limited to, poly(N-acetylglucosamine)(Chitin), Chitosan, poly(hydroxyvalerate), poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide),poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid),poly(L-lactide-co-glycolide); poly(D,L-lactide), poly(caprolactone),poly(trimethylene carbonate), polyethylene amide, polyethylene acrylate,poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters)(e.g. PEO/PLA), polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers otherthan polyacrylates, vinyl halide polymers and copolymers (such aspolyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether),polyvinylidene halides (such as polyvinylidene chloride),polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such aspolystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose.

Additional representative examples of polymers that may be especiallywell suited for use as a fiber material, particle material, or for anon-fibrous layer material for a medical device according to the methodsdisclosed herein include ethylene vinyl alcohol copolymer (commonlyknown by the generic name EVOH or by the trade name EVAL), poly(butylmethacrylate), poly(vinylidene fluoride-co-hexafluoropropene) (e.g.,SOLEF 21508, available from Solvay Solexis PVDF, Thorofare, N.J.),polyvinylidene fluoride (otherwise known as KYNAR, available fromATOFINA Chemicals, Philadelphia, Pa.), ethylene-vinyl acetatecopolymers, and polyethylene glycol. Representative examples of metallicmaterials or alloys that may be used for a non-fibrous layer of amedical device include, but are not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g.,BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.

For example, a stainless steel tube or sheet may be Alloy type: 316L SS,Special Chemistry per ASTM F138-92 or ASTM F139-92 grade 2. SpecialChemistry of type 316L per ASTM F138-92 or ASTM F139-92 Stainless Steelfor Surgical Implants in weight percent. An exemplary weight percent maybe as follows: Carbon (C): 0.03% max; Manganese (Mn): 2.00% max;Phosphorous (P): 0.025% max.; Sulphur (S):

0.010% max.; Silicon (Si): 0.75% max.; Chromium (Cr): 17.00-19.00%;Nickel (Ni): 13.00-15.50%; Molybdenum (Mo): 2.00-3.00%; Nitrogen (N):0.10% max.; Copper (Cu): 0.50% max.; Iron (Fe): Balance.

Drugs or therapeutic active agent(s) can include anti-inflammatories,antiproliferatives, and other bioactive agents.

An antiproliferative agent can be a natural proteineous agent such as acytotoxin or a synthetic molecule. Preferably, the active agents includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich 1001 West Saint PaulAvenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck)(synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁), all taxoids such astaxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimusdrugs such as macrolide antibiotics, rapamycin, everolimus, structuralderivatives and functional analogues of rapamycin, structuralderivatives and functional analogues of everolimus, FKBP-12 mediatedmTOR inhibitors, biolimus, perfenidone, prodrugs thereof, co-drugsthereof, and combinations thereof. Representative rapamycin derivativesinclude 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578 manufactured by AbbottLaboratories, Abbott Park, Ill.), prodrugs thereof, co-drugs thereof,and combinations thereof. In one embodiment, the anti-proliferativeagent is everolimus.

An anti-inflammatory drug can be a steroidal anti-inflammatory agent, anonsteroidal anti-inflammatory agent, or a combination thereof. In someembodiments, anti-inflammatory drugs include, but are not limited to,alclofenac, alclometasone dipropionate, algestone acetonide, alphaamylase, amcinafal, amcinafide, amfenac sodium, amiprilosehydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazidedisodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, deflazacort, desonide,desoximetasone, dexamethasone dipropionate, diclofenac potassium,diclofenac sodium, diflorasone diacetate, diflumidone sodium,diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide,endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate,felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal,fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid,flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortinbutyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasolpropionate, halopredone acetate, ibufenac, ibuprofen, ibuprofenaluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacinsodium, indoprofen, indoxole, intrazole, isoflupredone acetate,isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam,loteprednol etabonate, meclofenamate sodium, meclofenamic acid,meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone,methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone,piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazolecitrate, rimexolone, romazarit, salcolex, salnacedin, salsalate,sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap,tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylicacid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus,pimecorlimus, prodrugs thereof, co-drugs thereof, and combinationsthereof. In one embodiment, the anti-inflammatory agent is clobetasol.

Alternatively, the anti-inflammatory may be a biological inhibitor ofproinflammatory signaling molecules. Anti-inflammatory biological agentsinclude antibodies to such biological inflammatory signaling molecules.

In addition, drugs or active can be other than antiproliferative agentsor anti-inflammatory agents. These active agents can be any agent whichis a therapeutic, prophylactic, or a diagnostic agent. In someembodiments, such agents may be used in combination withantiproliferative or anti-inflammatory agents. These agents can alsohave anti-proliferative and/or anti-inflammmatory properties or can haveother properties such as antineoplastic, antiplatelet, anti-coagulant,anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic,antioxidant, and cystostatic agents. Examples of suitable therapeuticand prophylactic agents include synthetic inorganic and organiccompounds, proteins and peptides, polysaccharides and other sugars,lipids, and DNA and RNA nucleic acid sequences having therapeutic,prophylactic or diagnostic activities. Nucleic acid sequences includegenes, antisense molecules which bind to complementary DNA to inhibittranscription, and ribozymes. Some other examples of other bioactiveagents include antibodies, receptor ligands, enzymes, adhesion peptides,blood clotting factors, inhibitors or clot dissolving agents such asstreptokinase and tissue plasminogen activator, antigens forimmunization, hormones and growth factors, oligonucleotides such asantisense oligonucleotides and ribozymes and retroviral vectors for usein gene therapy. Examples of antineoplastics and/or antimitotics includemethotrexate, azathioprine, vincristine, vinblastine, fluorouracil,doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn,Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers SquibbCo., Stamford, Conn.). Examples of such antiplatelets, anticoagulants,antifibrin, and antithrombins include sodium heparin, low molecularweight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, thrombin inhibitors such as Angiomax ä (Biogen,Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), nitric oxide ornitric oxide donors, super oxide dismutases, super oxide dismutasemimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),estradiol, anticancer agents, dietary supplements such as variousvitamins, and a combination thereof. Examples of such cytostaticsubstance include angiopeptin, angiotensin converting enzyme inhibitorssuch as captopril (e.g. Capoten® and Capozide® from Bristol-Myers SquibbCo., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® andPrinzide® from Merck & Co., Inc., Whitehouse Station, N.J.). An exampleof an antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate include alpha-interferon,and genetically engineered epithelial cells. The foregoing substancesare listed by way of example and are not meant to be limiting.

Other bioactive agents may include antiinfectives such as antiviralagents; analgesics and analgesic combinations; anorexics;antihelmintics; antiarthritics, antiasthmatic agents; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihistamines;antimigrain preparations; antinauseants; antiparkinsonism drugs;

antipruritics; antipsychotics; antipyretics; antispasmodics;anticholinergics; sympathomimetics; xanthine derivatives; cardiovascularpreparations including calcium channel blockers and beta-blockers suchas pindolol and antiarrhythmics; antihypertensives; diuretics;vasodilators including general coronary; peripheral and cerebral;central nervous system stimulants; cough and cold preparations,including decongestants; hypnotics; immunosuppressives; musclerelaxants; parasympatholytics; psychostimulants; sedatives;tranquilizers; naturally derived or genetically engineered lipoproteins;and restenoic reducing agents. Other active agents which are currentlyavailable or that may be developed in the future are equally applicable.

EXAMPLES

The examples set forth below are for illustrative purposes only and arein no way meant to limit the invention. The following examples are givento aid in understanding the invention, but it is to be understood thatthe invention is not limited to the particular materials or proceduresof examples.

Example 1

2 wt % of high inherent viscosity PLLA in hexafluoroisopropanol waselectrospun utilizing voltages of +10 kV (nozzle) and −10 kV (mandrel),a flowrate of 1 mL/hr, over a distance of 10 cm onto a 4.0 mm stainlesssteel mandrel rotating at 3000 rpm for 30 min.

This PLLA 4.0 mm inner diameter fibrous tube was then annealed at 55° C.overnight on the mandrel in a vacuum oven to remove residual solvent.FIG. 14 depicts an image of the electrospun PLLA conduit or tube.

Example 2

A PLLA electrospun tube segment was cut and placed on carbon tape,sputter coated with gold-palladium and then imaged by scanning electronmicroscopy. Surface morphology consists of micron and sub-microndiameter fibers layered on one another. FIG. 15 depicts the surfacestructure of the electrospun PLLA conduit image from scanning electronmicroscopy (SEM).

Example 3

The PLLA 4.0 mm conduit of Examples 1-2 was laser cut. Retained fibermorphology was examined by scanning electron microscopy. FIGS. 16A-Cdepicts retained fiber morphology the laser cut implant.

Example 4

FIG. 17 depicts an SEM image of ˜200 nm PLGA nanoparticles loaded withApolipoprotein A-1 (ApoAl) mimetic peptide. ApoAl is an apolipoproteinand is the major protein component of high density lipoprotein (HDL) inplasma. It has been found the mimetic peptide functions similarly as thewild-type ApoAl protein.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. (canceled)
 2. A stent comprising: a stent scaffolding composed of apattern including a plurality of interconnecting fibrous struts, whereinthe fibrous struts are composed of a network of polymer fibers, whereinthe fibers have a thickness of 250 to 500 nm, wherein the fibrous strutsinclude particles that are encapsulated within the fibers, partiallyencapsulated within the fibers, and entrapped between the fibers of thefibrous struts, wherein the particles, fibers, or both comprise anactive agent.
 3. The stent of claim 2, wherein the polymer fibers areformed from a hydrogel, shape memory polymer, bioabsorbable polymer,biostable polymer, or a combination thereof
 4. The stent of claim 2,wherein the particles are formed from biostable polymer; a bioabsorbablepolymer; a biosoluble material; a biopolymer; a biostable metal; abioerodible metal; a block copolymer of a bioabsorbable polymer or abiopolymer; a ceramic material; a bioabsorbable glass; salts;fullerenes; lipids; and carbon nanotubes.
 5. The stent of claim 2,wherein the fibrous network exhibits shape memory properties.
 6. Thestent of claim 2, wherein an average pore size of the fibrous struts is250 nm-20 μm.
 7. The stent of claim 2, wherein a void fraction of thefibrous struts is 20-85%.
 8. The stent of claim 2, wherein aconcentration of particles in the struts is 0.5-50 vol %.
 9. The stentof claim 2, wherein the fibers are composed of poly(L-lactide).
 10. Thestent of claim 2, wherein the stent scaffolding is fabricated from atube composed of the network of polymer fibers by laser cutting thepattern in the tube.